Progesterone (pregn-4-ene-3,20-dione; P) and its metabolite 5α-pregnan-3α-ol-20-one (3α,5α-THP) are secreted by ovaries, adrenals, and glial cells. 3α,5α-THP in the midbrain ventral tegmental area mediates sexual receptivity of rodents through its actions at GABAA, NMDA, and/or D1 receptors. The extent to which 3α,5α-THP may influence anti-anxiety/anti-stress effects, conditioning and/or reward through these substrates and/or by altering hypothalamic pituitary adrenal axis function is discussed. Biosynthesis of 3α,5α-THP occurs in responses to mating and may underlie some of the rewarding aspects of sexual behavior. Recent findings from our laboratory which demonstrate that progestins can enhance approach to novel stimuli, conditioning, and reinforcement are reviewed. How progestins' effects on these processes may underlie response to drugs of abuse is considered and new findings which demonstrate interactions between progestins and cocaine are presented.